The goal of this research project is to discover new small molecule antiviral drugs that target essential regulatory functions encoded by the Human Immunodeficiency Virus (HIV) viral proteins and RNAs. The HIV-1 genome encodes protein (Tat) and RNA (TAR) elements that positively regulate transcriptional elongation off the HIV-1 promoter. The Rev protein and RRE RNA promote the nucleocytoplamic export of fully spliced viral RNA. If we could inhibit Tat-dependent transactivation of the HIV promoter and Rev dependent mRNA export, it would be possible to shut off viral replication both in acutely and in chronically infected cells. If this was achieved, viral replication within the reservoir of slowly replicating viruses that sustain infection even in the presence of Highly Active Anti Retroviral Therapy (HAART) would be depressed. Compounds that inhibit these viral functions would provide particularly attractive new approaches to combination treatment of drug-resistant HIV-1 strains. We propose to adopt a peptidomimetic approach grounded in structure-based design by pursuing the following specific objectives: 1. Use constrained cyclic peptide mimics of the Tat and Rev proteins to inhibit the HIV-1 Tat-TAR and Rev-RRE interactions; 2. Demonstrate activity of the peptide-like leads in vitro and in cell-based assays for viral replication; 3. Use structure-based drug design methods to reduce the cyclic peptides to potent small molecule mimics using peptidomimetic concepts. While the project is challenging and partly untested, the introduction of new structures leading to therapeutic options for treating drug-resistant viruses would have substantial impact.